Francis Crick
Francis Harry Compton Crick (8 June, 1916 – 28 July, 2004) was an English physicist, molecular biologist and neuroscientist, most noted for being one of the co-discoverers of the structure of the DNA molecule in 1953. He, James D. Watson, and Maurice Wilkins were jointly awarded the 1962 Nobel Prize for Physiology or Medicine "for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material".The Nobel Prize in Physiology or Medicine 1962. Nobel Prize Site for Nobel Prize in Physiology or Medicine 1962. His later work at the MRC Laboratory of Molecular Biology until 1977 has not received as much formal recognition. His remaining career as the J.W. Kieckhefer Distinguished Research Professor at the Salk Institute for Biological Studies was spent in La Jolla, California, until his death; "He was editing a manuscript on his death bed, a scientist until the bitter end" (a quote from his close associate Christof Koch ). Biography, family and education , in Cambridge, commemorating Francis Crick and representing the structure of DNA.]] Francis Crick was born, the firstson of Harry and Alex Elisabeth Crick (nee Wilkins), and raised in Weston Favell a small village near the English town of Northampton where Crick’s father and uncle ran the family’s boot and shoe factory. At an early age he was attracted to science and what he could learn about it from books. As a child he was taken to church (Congregationalist) by his parents, but by about age 12 he told his mother that he no longer wanted to attend. Crick preferred the scientific search for answers over belief in any dogma. He was educated at Northampton Grammar School (now Northampton School For Boys) and, after the age of 14, Mill Hill School in London (on scholarship) where he studied mathematics, physics and chemistry. At the age of 21, Crick earned a B.Sc. degree in physics from University College London (UCL).Chapters 1 and 2 of What Mad Pursuit: A Personal View of Scientific Discovery by Francis Crick (Basic Books reprint edition, 1990 ISBN 0-465-09138-5) provide Crick's description of his early life and education. Unfortunately, he had failed to gain a place at a Cambridge college as he wanted to, probably through falling foul of their requirement for Latin; his contemporaries in British DNA research Rosalind Franklin and Maurice Wilkins both went up to Cambridge colleges, to Newnham and St. John's colleges respectively. Crick began a Ph.D. research project on measuring viscosity of water at high temperatures (what he later described as "the dullest problem imaginable"Page 13 of What Mad Pursuit by Francis Crick.) in the laboratory of physicist Edward Neville da Costa Andrade, but with the outbreak of World War II, Crick was deflected from a possible career in physics. During World War II, he worked for the Admiralty Mining Establishment, from which emerged a group of many notable scientists; he worked on the design of magnetic and acoustic mines and was instrumental in designing a new mine that was effective against German minesweepers. After the war's end, Crick began studying biology in 1947 and became part of an important migration of physical scientists into biology research. This migration was made possible by the newly won influence of physicists such as Sir John Randall, who had helped win the war with inventions like radar. Crick had to adjust from the "elegance and deep simplicity" of physics to the "elaborate chemical mechanisms that natural selection had evolved over billions of years." He described this transition as, "almost as if one had to be born again." According to Crick, the experience of learning physics had taught him something important—hubris—and the conviction that since physics was already a success, great advances should also be possible in other sciences like biology. Crick felt that this attitude encouraged him to be more daring than typical biologists who mainly concerned themselves with the daunting problems of biology and not the past successes of physics. For the better part of two years Crick worked on the physical properties of cytoplasm at Cambridge's Strangeways Laboratory, headed by Honor Bridget Fell, with a Medical Research Council studentship, until he joined Perutz and Kendrew at the Cavendish. The Cavendish Laboratory at Cambridge was under the general direction of Sir Lawrence Bragg, a Nobel Prize winner at the age of 25 in 1915; Bragg was influential on the determination of DNA's structure to beat the leading American chemist Linus Pauling to the discovery. At the same time Bragg's Cavendish Laboratory was also effectively competing with King's College London under Sir John Randall. (Randall had turned down Francis Crick from working at King's College London.) Francis Crick and Maurice Wilkins of King's College London were personal friends, which influenced subsequent scientific events. *Spouses: Ruth Doreen Dodd Crick (m. 1940, div. 1947), Odile Speed Crick (m. 1949) *Children: Michael F. C. Crick, Gabrielle A. Crick, Jacqueline M. T. Crick Biology Research Crick was interested in two fundamental unsolved problems of biology. First, how molecules make the transition from the non-living to the living, and second, how the brain makes a conscious mind.Page 17 of What Mad Pursuit by Francis Crick. He realized that his background made him more qualified for research on the first topic and the field of biophysics. It was at this time of Crick’s transition from physics into biology that he was influenced by both Linus Pauling and Erwin Schrödinger.Page 18 of What Mad Pursuit by Francis Crick. It was clear in theory that covalent bonds in biological molecules could provide the structural stability needed to hold genetic information in cells. It only remained as an exercise of experimental biology to discover exactly which molecule was the genetic molecule.Page 22 of What Mad Pursuit by Francis Crick.Page 30 of The Eighth Day of Creation: Makers of the Revolution in Biology by Horace Freeland Judson published by Cold Spring Harbor Laboratory Press (1996) ISBN 0-87969-478-5. In Crick’s view, Charles Darwin’s theory of evolution by natural selection, Gregor Mendel’s genetics and knowledge of the molecular basis of genetics, when combined, reveal the secret of life.Page 25 of What Mad Pursuit by Francis Crick. It was clear that some macromolecule such as protein was likely to be the genetic molecule.Page 32 of What Mad Pursuit by Francis Crick. However, it was well known that proteins are structural and functional macromolecules some of which carry out enzymatic reactions of cells. In the 1940s, some evidence had been found pointing to another macromolecule, DNA, the other major component of chromosomes, as a candidate genetic molecule. Oswald Avery and his collaborators showed that a phenotypic difference could be caused in bacteria by providing them with a particular DNA molecule. However, other evidence was interpreted as suggesting that DNA was structurally uninteresting and possibly just a molecular scaffold for the apparently more interesting protein molecules.Pages 33-34 of What Mad Pursuit by Francis Crick. Crick was in the right place, in the right frame of mind, at the right time (1949) to join Max Perutz’s project at Cambridge University, and he began to work on the X-ray crystallography of proteins.Chapter 4 of What Mad Pursuit by Francis Crick. X-ray crystallography theoretically offered the opportunity to reveal the molecular structure of large molecules like proteins and DNA, but there were serious technical problems then preventing X-ray crystallography from being applicable to such large molecules. X-ray crystallography 1949-1950 Crick taught himself the mathematical theory of X-ray crystallography. During the time when Crick was learning about X-ray diffraction, researchers in the Cambridge lab were attempting to determine the most stable helical conformation of amino acid chains in proteins (the α helix). Pauling was the first to identify the 3.6 amino acids/turn ratio of the α helix. Crick was witness to the kinds of errors that his co-workers made in their failed attempts to make a correct molecular model of the α helix; these turned out to be important lessons that could be applied to the helical structure of DNA. For example, he learned the importance of the structural rigidity that double bonds confer on molecular structures which is relevant both to peptide bonds in proteins and the structure of nucleotides in DNA. double-helix pattern]] The Double Helix 1951-1953 In 1951, together with W. Cochran and V. Vand, Crick helped to work out a mathematical theory of X-ray diffraction by a helical molecule.Cochran W, Crick FHC and Vand V. (1952) "The Structure of Synthetic Polypeptides. I. The Transform of Atoms on a Helix", Acta Cryst., 5', 581-586. This theoretical result matched well with X-ray data obtained for proteins that contain sequences of amino acids in the Alpha helix conformation (published in Nature in 1952).See "''Evidence for the Pauling-Corey alpha-Helix in Synthetic Polypeptides" (1952)'' Nature'' Volume 169 pages 234-235 (download PDF). Crick's scientific publications and letters are in the list of Francis Crick's Papers from the Wellcome Library or the National Library of Medicine. Helical diffraction theory turned out to also be useful for understanding the structure of DNA. Late in 1951, Crick started working with James D. Watson at Cavendish Laboratory at the University of Cambridge in England. Using the X-ray diffraction results of Maurice Wilkins, Raymond Gosling and Rosalind Franklin of King's College London, Watson and Crick together developed a model for a helical structure of DNA, which they published in 1953,Molecular structure of Nucleic Acids by James D. Watson and Francis H. C. Crick. Nature '''171, 737–738 (1953). for this and subsequent work they were awarded the Nobel Prize in Physiology or Medicine in 1962, jointly with Maurice Wilkins.Francis Crick's 1962 Biography from the Nobel foundation. When James D. Watson came to Cambridge, Crick was a 35 year old graduate student and Watson was only 23, but he already had a Ph.D. They shared an interest in the fundamental problem of learning how genetic information might be stored in molecular form.Crick traced his interest in the physical nature of the gene back to the start of his work in biology when he was in the Strangeways laboratory; Page 22 of What Mad Pursuit by Francis Crick.In The Eighth Day of Creation, Horace Judson describes the development of Watson's thinking about the physical nature of genes. On page 89, Judson explains that by the time Watson came to Cambridge he believed genes were made of DNA and he hoped that he could use x-ray diffraction data to determine the structure. Watson and Crick talked endlessly about DNA and the idea that it might be possible to guess a good molecular model of its structure.Page 22 of What Mad Pursuit by Francis Crick. A key piece of experimentally-derived information came from X-ray diffraction images that had been obtained by Maurice Wilkins and his research student, Raymond Gosling. In November 1951 Wilkins came to Cambridge and shared his data with Watson and Crick. Alexander Stokes (another expert in helical diffraction theory) and Wilkins (both at King's College) had reached the conclusion that X-ray diffraction data for DNA indicated that the molecule had a helical structure. Stimulated by Wilkins, and a talk given by Rosalind Franklin about her work on DNA, Crick and Watson produced and showed off an erroneous first model of DNA. Watson, in particular thought they were competing against Pauling and feared that Pauling might determine the structure of DNA.Page 90, In The Eighth Day of Creation by Horace Judson. Many have speculated about what might have happened had Pauling been able to travel to Britain as planned in May of 1952.Linu Pauling and the Race for DNA: A Documentary History Special Collections, The Valley Library, Oregon State University. He might have seen some of the Wilkins/Gosling/Franklin X-ray diffraction data and it may have led him to a double helix model. As it was, his political activities caused his travel to be restricted by the U. S. government and he did not visit the UK until later and he met none of the DNA researchers in England at that time.Chapter 3 in The Eighth Day of Creation by Horace Judson. Watson and Crick were not officially working on DNA. Crick was writing his Ph.D. thesis. Watson also had other work such as trying to obtain crystals of myoglobin for X-ray diffraction experiments. In 1952 Watson did X-ray diffraction on tobacco mosaic virus and found results indicating that it had helical structure. Having failed once, Watson and Crick were now somewhat reluctant to try again and for a while they were forbidden to make further efforts to find a molecular model of DNA. Of great importance to the model building effort of Watson and Crick was Rosalind Franklin's understanding of basic chemistry which indicated that the hydrophilic phosphate backbones of the nucleotide chains of DNA should be positioned so as to interact with water molecules on the outside of the molecule while the hydrophobic bases should be packed into the core. Franklin shared this chemical knowledge with Watson and Crick when she pointed out to them that their first model (1951, with the phosphates inside) was obviously wrong. Crick described the failure of Maurice Wilkins and Rosalind Franklin to cooperate and work towards finding a molecular model of DNA as a major reason why he and Watson eventually made a second attempt to make a molecular model of DNA. They asked for and received permission to do so from both Bragg and Wilkins. In order to construct their model of DNA Watson and Crick made use of information from unpublished X-ray diffraction images (shown at meetings and shared by Wilkins) and preliminary accounts of Franklin's detailed analysis of the X-ray images that were included in a written progress report for the King's College laboratory of John Randall from late 1952. It is a matter of debate if Watson and Crick should have had access to Franklin's results before she had a chance to formally publish the results of her detailed analysis of her X-ray diffraction data that were included in the progress report. In an effort to clarify this issue, Perutz later published"DNA helix" by M. F. Perutz, J. T. Randall, L. Thomson, M. H. Wilkins J. D. Watson in Science (1969) Volume 164 pages 1537-1539. what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk (attended by Watson) in late 1951. Further, Perutz explained that the report was to a Medical Research Council committee that had been created in order to "establish contact between the different groups of working for the Council". Randall's and Perutz's labs were both MRC funded laboratories. It is also not clear how important Franklin's unpublished results that were in the progress report actually were for the model building done by Watson and Crick. After the first crude X-ray diffraction images of DNA were collected in the 1930s, William Astbury had talked about stacks of nucleotides spaced at 3.4 angstrom (0.34 nanometre) intervals in DNA. A citation to Astbury's earlier X-ray diffraction work was one of only 8 references in Franklin's first paper on DNA.Franklin's citation to the earlier work of W. T. Astbury is in "Molecular Configuration in Sodium Thymonucleate" by R. Franklin and R. G. Gosling in Nature (1953) volume 171 pages 740-741. The full text of this article is available for download in PDF format. Analysis of Astbury's published DNA diffraction data and the better X-ray diffraction images collected by Wilkins, Gosling and Franklin revealed the helical nature of DNA. It was possible to predict the number of bases stacked within a single turn of the DNA helix (10 per turn; a full turn of the helix is 27 angstroms nm in the compact A form, 34 angstroms nm in the wetter B form). Wilkins shared this information about the B form of DNA with Crick and Watson. One of the few references cited by Watson and Crick when they published their model of DNA was to a published article that included Sven Furberg’s DNA model that had the bases on the inside. Thus, the Watson and Crick model was not the first "bases in" model to be published. Furberg's results had also provided the correct orientation of the DNA sugars with respect to the bases. During their model building, Crick and Watson learned that an antiparallel orientation of the two nucleotide chain backbones worked best to orient the base pairs in the centre of a double helix. Crick's access to Franklin's progress report of late 1952 is what made Crick confident that DNA was a double helix with anti-parallel chains, but there were other chains of reasoning and sources of information that also led to these conclusions. When it became clear to Wilkins and the supervisors of Watson and Crick that Franklin was abandoning her work on DNA for a new job and that Pauling was working on the structure of DNA, they were willing to share Franklin's data with Watson and Crick in the hope that they could find a good model of DNA before Pauling. Franklin's X-ray diffraction data for DNA and her systematic analysis of DNA's structural features was useful to Watson and Crick in guiding them towards a correct molecular model. The key problem for Watson and Crick, that could not be resolved by the data from King's College, was to guess how the nucleotide bases pack into the core of the DNA double helix. Another key to finding the correct structure of DNA was the so-called Chargaff ratios, experimentally determined ratios of the nucleotide subunits of DNA: the amount of guanine is equal to cytosine and the amount of adenine is equal to thymine. A visit by Erwin Chargaff to England in 1952 helped keep this important fact in front of Watson and Crick. The significance of these ratios for the structure of DNA were not recognized until Watson, persisting in building structural models, realized that A:T and C:G pairs are structurally similar. In particular, the length of each base pair is the same. The base pairs are held together by hydrogen bonds, the same non-covalent interaction that stabilizes the protein α helix. Watson’s recognition of the A:T and C:G pairs was aided by information from Jerry DonohueSee Chapter 3 of The Eighth Day of Creation: Makers of the Revolution in Biology by Horace Freeland Judson published by Cold Spring Harbor Laboratory Press (1996) ISBN 0-87969-478-5. Judson also lists the publications of W. T. Astbury that described his early X-ray diffraction results for DNA. about the most likely structures of the nucleobases. After the discovery of the hydrogen bonded A:T and C:G pairs, Watson and Crick soon had their double helix model of DNA with the hydrogen bonds at the core of the helix providing a way to unzip the two complementary strands for easy replication: the last key requirement for a likely model of the genetic molecule. As important as Crick’s contributions to the discovery of the double helical DNA model were, he stated that without the chance to collaborate with Watson, he would not have found the structure by himself. Crick did tentatively attempt to perform some experiments on nucleotide base pairing, but he was more of a theoretical biologist than one who would perform experiments. There was another close approach to discovery of the base pairing rules in early 1952. Crick had started to think about interactions between the bases. He asked John Griffith to try to calculate attractive interactions between the DNA bases from chemical principles and quantum mechanics. Griffith's best guess was that A:T and G:C were attractive pairs. At that time, Crick was not aware of Chargaff's rules and he made little of Griffith's calculations. It did start him thinking about complementary replication. Identification of the correct base-pairing rules (A-T, G-C) was achieved by Watson "playing" with cardboard cut-out models of the nucleotide bases, much in the manner that Pauling had discovered the protein alpha helix a few years earlier. The Watson and Crick discovery of the DNA double helix structure was made possible by their correct interpretation of the significance of experimental results that had been obtained by others. Molecular Biology In 1954, Crick completed his Ph.D. thesis: "X-Ray Diffraction: Polypeptides and Proteins" and received his degree at the age of 37. Crick then worked in the laboratory of David Harker at Brooklyn Polytechnic Institute where he continued to develop his skills in the analysis of X-ray diffraction data for proteins, working primarily on ribonuclease and the mechanisms of protein synthesis. After the discovery of the double helix model of DNA, Crick’s interests quickly turned to the biological implications of the structure. In 1953, Watson and Crick published another article in Nature which stated: "it therefore seems likely that the precise sequence of the bases is the code that carries the genetical information"."Genetical implications of the structure of deoxyribonucleic acid" by J. D. Watson and F. H. C. Crick (1953) in Nature Volume 171 pages 964-967. In 1956 he and James Watson speculated on the structure of small viruses. They suggested that spherical viruses such as Tomato Bushy Stunt Virus had icosahedral symmetry and were made from 60 identical subunits.* . After his short time in New York, Crick returned to Cambridge where he worked until moving to California in 1976. Crick engaged in several X-ray diffraction collaborations such as one with Alexander Rich on the structure of collagen."The structure of collagen" by A Rich and F. H. C. Crick in Nature (1955) Volume 176, pages 915-916. However, Crick was quickly drifting away from continued work related to his expertise in the interpretation of X-ray diffraction patterns of proteins. George Gamow established a group of scientists who were interested in the role of RNA as an intermediary between DNA as the genetic storage molecule in the nucleus of cells and the synthesis of proteins in the cytoplasm. It was clear to Crick that there had to be a code by which a short sequence of nucleotides would specify a particular amino acid in a newly synthesized protein. In 1956 Crick wrote an informal paper about the genetic coding problem for the small group of scientists in Gamow’s RNA group."On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club" by Francis Crick (1956). In this article, Crick reviewed the evidence supporting the idea that there was a common set of about 20 amino acids used to synthesize proteins. Crick proposed that there was a corresponding set of small adaptor molecules that would hydrogen bond to short sequences of a nucleic acid and also link to one of the amino acids. He also explored the many theoretical possibilities by which short nucleic acid sequences might code for the 20 amino acids. molecule. Crick predicted that such adaptor molecules might exist as the links between codons and amino acids.]] During the mid-to-late 1950s Crick was very much intellectually engaged in sorting out the mystery of how proteins are synthesized. By 1958 Crick’s thinking had matured and he could list in an orderly way all of the key features of the protein synthesis process:"On protein synthesis" by F. H. C. Crick in Symp Soc Exp Biol. (1958);12:138-63. *genetic information stored in the sequence of DNA molecules *a “messenger” RNA molecule to carry the instructions for making one protein to the cytoplasm *adaptor molecules (“they might contain nucleotides”) to match short sequences of nucleotides in the RNA messenger molecules to specific amino acids *ribonucleic-protein complexes that catalyse the assembly of amino acids into proteins according to the messenger RNA The “adaptor molecules” were eventually shown to be tRNAs and the catalytic “ribonucleic-protein complexes” became known as ribosomes. An important step was later (1960) realization that the messenger RNA was not the same as the ribosomal RNA. None of this, however, answered the fundamental theoretical question of the exact nature of the genetic code. In his 1958 article, Crick speculated, as had others, that a triplet of nucleotides could code for an amino acid. Such a code might be “degenerate”, with 4x4x4=64 possible triplets of the four nucleotide subunits while there were only 20 amino acids. Some amino acids might have multiple triplet codes. Crick also explored other codes in which for various reasons only some of the triplets were used, “magically” producing just the 20 needed combinations. Experimental results were needed; theory alone could not decide the nature of the code. Crick also used the term “central dogma” to summarize an idea that implies that genetic information flow between macromolecules would be essentially one-way: DNA → RNA → Protein Some critics thought that by using the word "dogma" Crick was implying that this was a rule that could not be questioned, but all he really meant was that it was a compelling idea without much solid evidence to support it. In his thinking about the biological processes linking DNA genes to proteins, Crick made explicit the distinction between the materials involved, the energy required and the information flow. Crick was focused on this third component (information) and it became the organizing principle of what became known as molecular biology. Crick had by this time become a dominant, if not the dominant, theoretical molecular biologist. Proof that the genetic code is a degenerate triplet code finally came from genetics experiments, some of which were performed by Crick."General nature of the genetic code for proteins" by F. H. C. Crick, L. Barnett, S. Brenner and R. J. Watts-Tobin in Nature (1961) Volume 192 pages 1227-1232. The details of the code came mostly from work by Marshall Nirenberg and others who synthesized synthetic RNA molecules and used them as templates for in vitro protein synthesis"[http://profiles.nlm.nih.gov/SC/B/C/B/X/_/